This program project grant (PPG) application is an integrative endeavor by the Emory Center for Transfusion and Cellular Therapies to institute a major, interdisciplinary, and synergistic research effort to improve the safety and effectiveness of blood dell transfusions, particularly in immuno-compromised transfusion recipients. The central theme is to address mechanisms of, and mitigate the effects of, several of the most serious causes of morbidity and mortality in transfusion medicine, including GVHD following cellular therapies, opportunistic and transfusion-transmitted infections including CMV, and immunization to RBC antigens in recipients of multiple transfusions. Each project uses innovative and novel approaches, strategies and/or technologies to address the central theme including vaccine enhanced- (Project 1) and pharmacologically modified- (Project 3) donor lymphocyte infusions, nucleic acid testing and automated capillary cytometric leukocyte counting (Project 2), and a genetically engineered murine model allowing a step-by-step analysis of the cellular and molecular pathways to RBG immunization (Project 4). In brief, Project 1 extends our previous studies with a mouse BMT model by developing a novel method of combining donor lymphocyte infusion (DLI) with an effective listeria-based vaccination strategy. Project 2 is a multihospital trial, proposed in conjunction with more basic laboratory studies, designed to validate optimized methods to prevent transfusion-transmitted GMV infections. Project 3 extends our previous studies with a mouse BMT model and employs in humans a novel strategy to adoptively transfer antigen-specific donor T-cells without inducing lethal GVHD. Project 4 utilizes a novel murine model of RBC immunization developed in our laboratories to identify the cellular and molecular events that regulate immune responses to transfused RBC. The team of investigators in the PPG spans Public Health, Oncology, Hematology, Pediatrics, and Blood Banking disciplines and has worked together to create a series of synergistic proposals. As each of these 4 projects addresses important cellular and immunologic events in Transfusion Medicine, project completion should lead to novel, improved transfusion and transplantation therapeutic components and/or strategies to protect high-risk transfusion recipients. The successful execution of the Projects will be facilitated by three Cores including an Administrative Core (Core A), an Immunologic and Virologic Monitoring Laboratory Core (Core B), and a Biostatistics and Data Management Gore (Core G).